1. Field of the Invention
The present invention relates to human endogenous retroviruses, fragments thereof, a biologically functional vector comprising sequences of said retrovirus.
2. Description of Related Art
Endogenous retroviruses (ERVs) are integral parts in the genomes of many, if not of all, species. ERVs most probably, resulted from infection of germ line cells with exogenous retroviruses and subsequent fixation of their genetic information in the host genome.
Many types of human endogenous retroviruses (HERVs) have been characterized previously, and they have been classified into different groups, or families, partly on the basis of their sequence identity and partly according to the similarity of their primer binding sites (PBSs) to host tRNAs. Thus, members of the HERV.H family contain a PBS with a sequence similar to a region of tRNAHis, whereas the HERV.E family is primed by tRNAGlu. Despite the large amount of data available, the classification of the many different HERV families within an overall phylogenetic framework has been hampered for several reasons: (i) some highly divergent retroviruses are primed by the same type of tRNA; (ii) many HERV families have not been fully characterized, and the sequence information that has been reported is often derived from different genomic regions, making interfamily comparisons problematic; and (iii) the relative lack of sequence information on other host taxa has made it difficult to distinguish between genuinely monophyletic HERV families and polyphyletic families that appear monophyletic only because similar viruses in other hosts have not yet been described. A pathogenic potential of nondefective endogenous retroviruses has so far only been demonstrated in mice, in which they may induce tumors and immunological disorders. In human DNA, endogenous retrovirus sequences (HERVs) are well known genetic elements. They all seem to be defective due to multiple termination codons, deletions, or the lack of a 5′ long terminal repeat (LTR). Replication competent human endogenous retrovirus genomes have not yet been isolated.
Extensive studies on animal melanomas (especially that of the hamster), which serve as model for human malignant melanoma have shown the occurrence of virus particles in the tumors. A high molecular weight (70S) RNA species as well as an RNA-directed DNA polymerase, two diagnostic features for oncorna (oncogenic RNA) viruses have been associated with these particles. Cell-free transmission experiments end to the conclusion that hamster melanomas are caused by an RNA virus.
Based on these findings the working hypothesis was proposed that human melanoma may also have a viral etiology. In experiments the occurrence of virus-like particles as well as reverse transcriptase activity in metastases of human melanoma was reported in the early 70s. (Birkmayer et al., Europ. J. Cancer 10 (1974) 419-422).
These virus-like particles are spherical or slightly ovoid and have a diameter of 90-120 nm. They have an electron-dense nucleoid measuring 50-70 nm across and are bounded by a triple-layered, 100 Å thick membrane. Sometimes fine projections extend radially from the nucleoid towards the membrane, and in this case the particles resemble those found in hamster melanoma. Their number is rather small in comparison to that found in hamster melanoma. So far, they have been seen only in the cytoplasm and no infectivity has been observed for these particles (Birkmayer et al., Die Naturwissenschaften 59 (8) (1972), 369-370).
Also Balda et al. (Proc. Nat. Acad. Sci, USA 72 (9) (1975, 3697-3700) described a high molecular weight RNA encapsulated with an RNA extracted DNA polymerase in particles possessing the identity characteristic of the RNA tumor viruses which was detected in human malignant melanomas. However, also here no infectious particles were observed.
Only many years later the expression of a family of human endogenous retrovirus sequences (HERV-K) in GH cells, a teratocarcinoma cell line producing the human teratocarcinoma-derived retrovirus (HTDV) particles was described (Löwer et al., Proc. Natl. Acad. Sci. USA 90 (1993): 4480-4484). Detailed electron microscopic surveys have revealed the existence of retrovirus-like particles in human placentas and teratocarcinoma cell lines. However, these found HERV-K/HTDV particles were also not infectious: They possess a distinct morphology: (i) they lack the electron lucent space normally seen between viral envelope and core, (ii) they seem to be predominantly arrested in budding stages, and (iii) collapsed cores, a consequence of a final proteolytic step in virus maturation, have never been observed. As long as the gag precursor remains uncleaved, resulting particles are not likely to be infectious.
A further HERV-K provirus was shown to be present in gorilla and chimpanzee genomes but not in the human genome (Barbulescu et al., Current Biology 11 (10) (2001), 779-783).
Therefore, human endogenous retroviruses have shown to be expressed, however, these virus particles found up to date were all non-infectious virus particles. Some endogenous retrovirus-like particles were found to be expressed in melanoma cells. However, the only infectious endogenous retroviruses found were some animal endogenous retroviruses, e.g. MelARV, a retrovirus capable of infecting cultured murine melanocytes which have also been shown to induce in some instances malignant transformation.
In the article by Reus et al. (Journal of Virology, October 2001, 8917-8926) it is stated that the average age of HERV-K proviruses is ca. 28 million years. It is described that at that time the HERV-Ks probably used to be infectious.
The WO 01/62937 A1 relates to retrovirus sequences and psoriasis.
In the WO 00/53789 A1 various retroviral expression vectors are listed.
The WO 00/20460 A1 relates to the detection of a HERV-K10 gag-sequence which is brought into relationship with the cancer seminoma, whereby the HERV-K10 gag-sequence is used as tumor marker as well as for therapeutic methods.
In the WO 00/06598 A1 a HERV-AVL3-B sequence fragment is brought in connection with methods for the treatment for malign melanomas.
The WO 99/67395 A1 relates to a 600 bp sequence of an env-gene of a virus family HERV-7q and relates to the use for or in connection with multiple sclerosis, and autoimmune diseases, respectively.
In the WO 98/24454 A1 the use of a retroviral ribozyme sequence HERV-PTN for the inhibition of tumor growth is described.
The JP 9252780 A relates to a method, in which a retrovirus polypeptide of the type HERV-E as a surrogate marker for cancer and other illnesses is detected.
The WO 01/70941 A2 relates to a retroviral sequence with high homology to the family HERV-H, whereby this sequence is brought into connection with multiple sclerosis.
The DE 198 11 692 A1 relates to a preparation for the protection against sun rays which is effective against herpes simplex viruses, whereby the preparation comprises organic and anorganic light filters.